EP3523309B1 - Agents antibactériens contre d, d- et l, d-transpeptidases - Google Patents

Agents antibactériens contre d, d- et l, d-transpeptidases Download PDF

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EP3523309B1
EP3523309B1 EP17859990.8A EP17859990A EP3523309B1 EP 3523309 B1 EP3523309 B1 EP 3523309B1 EP 17859990 A EP17859990 A EP 17859990A EP 3523309 B1 EP3523309 B1 EP 3523309B1
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group
ldt
alkyl
compound
transpeptidases
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EP3523309A1 (fr
EP3523309A4 (fr
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Craig A. Townsend
Evan LLOYD
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Johns Hopkins University
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Johns Hopkins University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D499/887—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with a hetero atom or a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis

Definitions

  • Decades-old drugs comprise the standard regimens available today for the treatment of tuberculosis (TB), a disease caused by infection with Mycobacterium tuberculosis.
  • TB tuberculosis
  • WHO World Health Organization
  • Drug regimens that can reduce the complexity and duration of treatment and that also have activity against drug-resistant M. tuberculosis could significantly impact the control of TB and alleviate the suffering of patients with this disease.
  • ⁇ -lactam antibacterials which target peptidoglycan biosynthesis and are overall the most widely utilized class of antibacterials for the treatment of infections, have traditionally not been effective in TB treatment (Walsh, 2003).
  • This lack of activity against M . tuberculosis has primarily been attributed to the presence of the chromosomally-encoded ⁇ -lactamase enzyme BlaC, which hydrolyzes the core ⁇ -lactam ring to deactivate the drug (Hugonnet, et al., 2009) and also to the potential for limiting penetration of the thick mycolate coat (Wivagg, et al., 2014).
  • ⁇ -lactams specifically the carbapenems, as well as the penem faropenem, may have anti-TB activity (Cordillot, et al., 2013; Dhar, et al., 2015; Kaushik, et al., 2015; Rullas, et al., 2015).
  • these types of ⁇ -lactams are unique in that they target more than one enzyme involved in bacterial peptidoglycan synthesis.
  • D,D-transpeptidases commonly known as penicillin-binding proteins. These enzymes catalyze the formation of 4 ⁇ 3 transpeptide linkages in the peptidoglycan network. Emerging evidence suggests that carbapenems target not only the D,D-transpeptidases, but also the non-canonical L,D-transpeptidases, which catalyze the formation of 3 ⁇ 3 transpeptide linkages (Cordillot, et al., 2013; Gupta, et al., 2010; Erdemli, et al., 2012). This latter function may be key to the anti-TB activity observed with faropenem and carbapenems as M.
  • tuberculosis primarily uses L,D-transpeptidases to cross-link its peptidoglycan (Lavollay, et al., 2008; Kumar, et al., 2012) and mutants lacking the L,D-transpeptidases Ldt Mt1 and Ldt Mt2 are attenuated in virulence, have modified peptidoglycan, and altered cell physiology and morphology (Gupta, et al., 2010; Schoonmaker, et al., 2014). Kaushik et al., Antimicrobial Agents and Chemotherapy, volume 59, No.
  • the presently disclosed subject matter provides novel lactam antibacterial agents that contain a bicyclic penem core bearing substituents at the C-2 and C-6 positions.
  • Kinetics and x-ray structural studies verified that the presently disclosed compounds bind to L,D-transpeptidases (enzymes involved in the biosynthesis of the peptidoglycan layer that are distinct from classical D,D-transpeptidases) of several bacterial pathogens important to human health.
  • pathogens include Gram-positive, Gram-negative and acid-fast bacteria.
  • the presently disclosed compounds exhibit potent antimicrobial activity.
  • the present invention provides a compound of formula (Ic):
  • the presently disclosed subject-matter provides a method of inhibiting the growth of a bacterium in vitro comprising contacting the bacterium with an effective amount of the compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof.
  • the presently disclosed subject matter provides a compound of formula (Ic) for use in treating a bacterial infection or preventing a bacterial infection in a subject.
  • the presently disclosed subject matter provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (Ic) and a pharmaceutically acceptable carrier.
  • Bacterial survival requires an intact peptidoglycan layer, a 3-dimensional exoskeleton that encapsulates the cytoplasmic membrane. Historically, the final steps of peptidoglycan synthesis are known to be carried out by D,D-transpeptidases, enzymes that are inhibited by the ⁇ -lactams which constitute >50% of all antibacterials in clinical use.
  • the presently disclosed subject matter demonstrates that the carbapenem subclass of ⁇ -lactams is distinctly effective, not only because they inhibit D,D-transpeptidases and are poor substrates for ⁇ -lactamases, but primarily because they also inhibit non-classical transpeptidases, namely the L,D-transpeptidases, which generate the majority of linkages in the peptidoglycan of mycobacteria.
  • the presently disclosed subject matter in part, elucidates the molecular mechanisms responsible for inhibition of L,D-transpeptidases of M. tuberculosis and a range of bacteria, including ESKAPE pathogens. This information was leveraged to design, synthesize and test simplified carbapenems exhibiting potent antibacterial activity.
  • the presently disclosed subject matter characterized the inhibitory interactions using biochemical and biophysical approaches, including solving multiple crystal structures, of faropenem and carbapenems with the M. tuberculosis L,D-transpeptidases Ldt Mt1 and Ldt Mt2 and validated carbapenem anti-TB activity in vivo in a preclinical mouse model of TB treatment. Based on these data, structure-activity relationships could be analyzed and used to direct the synthesis of evolved carbapenems exhibiting potent activity against M. tuberculosis.
  • Q is selected from the group consisting of pyrrolidinyl, morpholinyl, and N-methylpiperazinyl.
  • P is selected from the group consisting of -N(R 6 )-, and -SO 2 -;
  • R 2 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, C 6 -C 12 aryl, and C 4 -C 16 alkylaryl;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and - SO 2 NR 3 R 4 ;
  • R 5 is selected from the group consisting of hydrogen, and C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, and C 4 -C 16 alkylaryl;
  • R 6 is selected from the group consisting of
  • the present invention provides a specific formula within the generic compound of formula (I), wherein the compound is a compound of formula (Ic): wherein P is -N(R 6 )-; and R 6 is and stereoisomers and pharmaceutically acceptable salts thereof.
  • the compound of formula (Ic) may be:
  • the compound of formula (Ia), disclosed herein for reference is selected from the group consisting of:
  • the compound of formula (Ia), disclosed herein for reference is selected from the group consisting of:
  • the presently invention provides a compound of formula (Ic), or stereoisomer, or pharmaceutically acceptable salt thereof, for use in treating or preventing a bacterial infection in a subject.
  • the present invention provides method of inhibiting the growth of a bacterium in vitro comprising contacting the bacterium with an effective amount of a compound of formula (Ic), or a stereoisomer or pharmaceutically acceptable salt thereof.
  • the term "treating" can include reversing, alleviating, inhibiting the progression of, preventing or reducing the likelihood of the disease, disorder, or condition to which such term applies, or one or more symptoms or manifestations of such disease, disorder or condition, including killing or eliminating an infectious agent, such as M. tuberculosis, M. abscessus, A. baumannii, S. aureus, K. pneumoniae, E. cloacae, P. aeruginosa and E. faecalis or a combination thereof.
  • the bacterial infection is one or more strains of bacteria that is resistant to antimicrobial agents directed to inactive D, D-transpeptidase.
  • Preventing refers to causing a disease, disorder, condition, or symptom or manifestation of such, or worsening of the severity of such, not to occur. Accordingly, the presently disclosed compounds can be administered prophylactically to prevent or reduce the incidence or recurrence of the disease, disorder, or condition.
  • a "subject” treated by the presently disclosed methods in their many embodiments is desirably a human subject, although it is to be understood that the methods described herein are effective with respect to all vertebrate species, which are intended to be included in the term "subject.” Accordingly, a “subject” can include a human subject for medical purposes, such as for the treatment of an existing condition or disease or the prophylactic treatment for preventing the onset of a condition or disease, or an animal subject for medical, veterinary purposes, or developmental purposes.
  • Suitable animal subjects include mammals including, but not limited to, primates, e.g., humans, monkeys, apes, and the like; bovines, e.g., cattle, oxen, and the like; ovines, e.g., sheep and the like; caprines, e.g., goats and the like; porcines, e.g., pigs, hogs, and the like; equines, e.g., horses, donkeys, zebras, and the like; felines, including wild and domestic cats; canines, including dogs; lagomorphs, including rabbits, hares, and the like; and rodents, including mice, rats, and the like.
  • mammals including, but not limited to, primates, e.g., humans, monkeys, apes, and the like; bovines, e.g., cattle, oxen, and the like; ovines, e.g., sheep and the like; cap
  • an animal may be a transgenic animal.
  • the subject is a human including, but not limited to, fetal, neonatal, infant, juvenile, and adult subjects.
  • a "subject” can include a patient afflicted with or suspected of being afflicted with a condition or disease.
  • the terms “subject” and “patient” are used interchangeably herein.
  • the term “subject” also refers to an organism, tissue, cell, or collection of cells from a subject.
  • the "effective amount" of an active agent or drug delivery device refers to the amount necessary to elicit the desired biological response.
  • the effective amount of an agent or device may vary depending on such factors as the desired biological endpoint, the agent to be delivered, the makeup of the pharmaceutical composition, the target tissue, and the like.
  • the term “combination” is used in its broadest sense and means that a subject is administered at least two agents, more particularly a compound of Formula (I) and one or more antibacterial agents. More particularly, the term “in combination” refers to the concomitant administration of two (or more) active agents for the treatment of a, e.g., single disease state.
  • the active agents may be combined and administered in a single dosage form, may be administered as separate dosage forms at the same time, or may be administered as separate dosage forms that are administered alternately or sequentially on the same or separate days.
  • the active agents are combined and administered in a single dosage form.
  • the active agents are administered in separate dosage forms (e.g., wherein it is desirable to vary the amount of one but not the other).
  • the single dosage form may include additional active agents for the treatment of the disease state.
  • the compounds of Formula (I) described herein can be administered alone or in combination with adjuvants that enhance stability of the compounds of Formula (I), alone or in combination with one or more antibacterial agents, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including other active ingredients.
  • combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies.
  • a subject administered a combination of a compound of Formula (I) and at least one additional therapeutic agent can receive compound of Formula (I) and at least one additional therapeutic agent at the same time (i.e., simultaneously) or at different times (i.e., sequentially, in either order, on the same day or on different days), so long as the effect of the combination of both agents is achieved in the subject.
  • agents administered sequentially can be administered within 1, 5, 10, 30, 60, 120, 180, 240 minutes or longer of one another. In other embodiments, agents administered sequentially, can be administered within 1, 5, 10, 15, 20 or more days of one another.
  • the compound of Formula (I) and at least one additional therapeutic agent are administered simultaneously, they can be administered to the subject as separate pharmaceutical compositions, each comprising either a compound of Formula (I) or at least one additional therapeutic agent, or they can be administered to a subject as a single pharmaceutical composition comprising both agents.
  • the effective concentration of each of the agents to elicit a particular biological response may be less than the effective concentration of each agent when administered alone, thereby allowing a reduction in the dose of one or more of the agents relative to the dose that would be needed if the agent was administered as a single agent.
  • the effects of multiple agents may, but need not be, additive or synergistic.
  • the agents may be administered multiple times.
  • the two or more agents when administered in combination, can have a synergistic effect.
  • the terms “synergy,” “synergistic,” “synergistically” and derivations thereof, such as in a “synergistic effect” or a “synergistic combination” or a “synergistic composition” refer to circumstances under which the biological activity of a combination of a compound of Formula (I) and at least one additional therapeutic agent is greater than the sum of the biological activities of the respective agents when administered individually.
  • a "synergistic combination” has an activity higher that what can be expected based on the observed activities of the individual components when used alone.
  • a “synergistically effective amount" of a component refers to the amount of the component necessary to elicit a synergistic effect in, for example, another therapeutic agent present in the composition.
  • the presently disclosed subject matter provides a method of inhibiting the growth of a bacteria in vitro comprising contacting the bacteria with an effective amount of a compound of formula (I), stereoisomer, or pharmaceutically acceptable salt thereof.
  • the term “inhibition” or “reduction” and grammatical derivations thereof refers to the ability of an agent to block, partially block, interfere, decrease, reduce or deactivate a biological molecule, pathway or mechanism of action.
  • the term “inhibit” encompasses a complete and/or partial loss of activity, e.g., a loss in activity by at least 10%, in some embodiments, a loss in activity by at least 20%, 30%, 50%, 75%, 95%, 98%, and up to and including 100%.
  • the present invnetion provides a pharmaceutical composition including one compounds of formula (Ic), alone or in combination with one or more additional therapeutic agents in admixture with a pharmaceutically acceptable excipient.
  • pharmaceutical compositions include the pharmaceutically acceptable salts of the compounds described above.
  • Pharmaceutically acceptable salts are generally well known to those of ordinary skill in the art, and include salts of active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituent moieties found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent or by ion exchange, whereby one basic counterion (base) in an ionic complex is substituted for another.
  • bases include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent or by ion exchange, whereby one acidic counterion (acid) in an ionic complex is substituted for another.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19 ).
  • Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • salts suitable for use with the presently disclosed subject matter include, by way of example but not limitation, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, carnsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate,
  • the compounds of the disclosure can be formulated for a variety of modes of administration, including systemic and topical or localized administration. Techniques and formulations generally may be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000 ).
  • agents may be formulated into liquid or solid dosage forms and administered systemically or locally.
  • the agents may be delivered, for example, in a timed- or sustained-slow release form as is known to those skilled in the art. Techniques for formulation and administration may be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000 ).
  • Suitable routes may include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra-articullar, intra -sternal, intra-synovial, intra-hepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or other modes of delivery.
  • the agents of the disclosure may be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • compositions of the present disclosure in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection.
  • the compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration.
  • Such carriers enable the compounds of the disclosure to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject (e.g., patient) to be treated.
  • the agents of the disclosure also may be formulated by methods known to those of skill in the art, and may include, for example, but not limited to, examples of solubilizing, diluting, or dispersing substances, such as saline; preservatives, such as benzyl alcohol; absorption promoters; and fluorocarbons.
  • compositions suitable for use in the present disclosure include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, the compounds according to the disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. A non-limiting dosage is 10 to 30 mg per day.
  • the exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, the bioavailability of the compound(s), the adsorption, distribution, metabolism, and excretion (ADME) toxicity of the compound(s), and the preference and experience of the attending physician.
  • these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • the preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.
  • compositions for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl- cellulose, sodium carboxymethyl-cellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone).
  • disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs).
  • PEGs liquid polyethylene glycols
  • stabilizers may be added.
  • substituted refers to the ability, as appreciated by one skilled in this art, to change one functional group for another functional group on a molecule, provided that the valency of all atoms is maintained.
  • substituent may be either the same or different at every position.
  • the substituents also may be further substituted (e.g., an aryl group substituent may have another substituent off it, such as another aryl group, which is further substituted at one or more positions).
  • R groups such as groups R 1 , R 2 , and the like, or variables, such as "m” and "n"
  • R 1 and R 2 can be substituted alkyls, or R 1 can be hydrogen and R 2 can be a substituted alkyl, and the like.
  • a when used in reference to a group of substituents herein, mean at least one.
  • a compound is substituted with "an” alkyl or aryl, the compound is optionally substituted with at least one alkyl and/or at least one aryl.
  • R substituent the group may be referred to as "R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different.
  • R or group will generally have the structure that is recognized in the art as corresponding to a group having that name, unless specified otherwise herein.
  • certain representative “R” groups as set forth above are defined below.
  • a "substituent group,” as used herein, includes a functional group selected from one or more of the following moieties, which are defined herein:
  • the term hydrocarbon refers to any chemical group comprising hydrogen and carbon.
  • the hydrocarbon may be substituted or unsubstituted. As would be known to one skilled in this art, all valencies must be satisfied in making any substitutions.
  • the hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic.
  • Illustrative hydrocarbons are further defined herein below and include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, and the like.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain, acyclic or cyclic hydrocarbon group, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent groups, having the number of carbon atoms designated (i.e., C 1 -C 10 means one to ten carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbons).
  • alkyl refers to C 1-20 inclusive, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbons, linear (i.e., "straight-chain"), branched, or cyclic, saturated or at least partially and in some cases fully unsaturated (i.e., alkenyl and alkynyl) hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom.
  • saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec- pentyl, isopentyl, neopentyl, n -hexyl, sec -hexyl, n -heptyl, n -octyl, n -decyl, n- undecyl, dodecyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologs and isomers thereof.
  • Branched refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain.
  • Lower alkyl refers to an alkyl group having 1 to about 8 carbon atoms (i.e., a C 1-8 alkyl), e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
  • Higher alkyl refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.
  • alkyl refers, in particular, to C 1-8 straight-chain alkyls. In other embodiments, “alkyl” refers, in particular, to C 1-8 branched-chain alkyls.
  • Alkyl groups can optionally be substituted (a "substituted alkyl") with one or more alkyl group substituents, which can be the same or different.
  • alkyl group substituent includes but is not limited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl.
  • alkyl chain There can be optionally inserted along the alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as "alkylaminoalkyl”), or aryl.
  • substituted alkyl includes alkyl groups, as defined herein, in which one or more atoms or functional groups of the alkyl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon group, or combinations thereof, consisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule.
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)NR', -NR'R", -OR', -SR, -S(O)R, and/or -S(O 2 )R'.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R” or the like.
  • Cyclic and “cycloalkyl” refer to a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.
  • the cycloalkyl group can be optionally partially unsaturated.
  • the cycloalkyl group also can be optionally substituted with an alkyl group substituent as defined herein, oxo, and/or alkylene.
  • cyclic alkyl chain There can be optionally inserted along the cyclic alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl, thus providing a heterocyclic group.
  • Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • Multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradamantyl, and fused ring systems, such as dihydro- and tetrahydronaphthalene, and the like.
  • cycloalkylalkyl refers to a cycloalkyl group as defined hereinabove, which is attached to the parent molecular moiety through an alkyl group, also as defined above.
  • alkyl group also as defined above.
  • examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.
  • cycloheteroalkyl or “heterocycloalkyl” refer to a non-aromatic ring system, unsaturated or partially unsaturated ring system, such as a 3- to 10-member substituted or unsubstituted cycloalkyl ring system, including one or more heteroatoms, which can be the same or different, and are selected from the group consisting of nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), and silicon (Si), and optionally can include one or more double bonds.
  • N nitrogen
  • O oxygen
  • S sulfur
  • P phosphorus
  • Si silicon
  • the cycloheteroalkyl ring can be optionally fused to or otherwise attached to other cycloheteroalkyl rings and/or non-aromatic hydrocarbon rings.
  • Heterocyclic rings include those having from one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • heterocylic refers to a non-aromatic 5-, 6-, or 7-membered ring or a polycyclic group wherein at least one ring atom is a heteroatom selected from O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), including, but not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring.
  • Representative cycloheteroalkyl ring systems include, but are not limited to pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinanyl, tetrahydrofuranyl, and the like.
  • heterocycloalkyl ring systems include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like.
  • cycloalkylene and “heterocycloalkylene” refer to the divalent derivatives of cycloalkyl and heterocycloalkyl, respectively.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • Alkyl groups which are limited to hydrocarbon groups are termed "homoalkyl.”
  • alkenyl refers to a monovalent group derived from a C 1-20 inclusive straight or branched hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen molecule.
  • Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, pentenyl, hexenyl, octenyl, allenyl, and butadienyl.
  • cycloalkenyl refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond.
  • Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.
  • alkynyl refers to a monovalent group derived from a straight or branched C 1-20 hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon triple bond.
  • alkynyl include ethynyl, 2-propynyl (propargyl), 1-propynyl, pentynyl, hexynyl, and heptynyl groups, and the like.
  • alkylene by itself or a part of another substituent refers to a straight or branched bivalent aliphatic hydrocarbon group derived from an alkyl group having from 1 to about 20 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.
  • the alkylene group can be straight, branched or cyclic.
  • the alkylene group also can be optionally unsaturated and/or substituted with one or more "alkyl group substituents.” There can be optionally inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as "alkylaminoalkyl”), wherein the nitrogen substituent is alkyl as previously described.
  • An alkylene group can have about 2 to about 3 carbon atoms and can further have 6-20 carbons. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being some embodiments of the present disclosure.
  • a "lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • heteroalkylene by itself or as part of another substituent means a divalent group derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroatoms also can occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like).
  • no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)OR'- represents both -C(O)OR'- and -R'OC(O)-.
  • aryl means, unless otherwise stated, an aromatic hydrocarbon substituent that can be a single ring or multiple rings (such as from 1 to 3 rings), which are fused together or linked covalently.
  • heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms (in each separate ring in the case of multiple rings) selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-iso
  • arylene and heteroarylene refer to the divalent forms of aryl and heteroaryl, respectively.
  • aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl and heteroarylalkyl are meant to include those groups in which an aryl or heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, furylmethyl, and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like).
  • haloaryl as used herein is meant to cover only aryls substituted with one or more halogens.
  • heteroalkyl where a heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (e.g. "3 to 7 membered"), the term “member” refers to a carbon or heteroatom.
  • a structure represented generally by the formula: as used herein refers to a ring structure, for example, but not limited to a 3-carbon, a 4-carbon, a 5-carbon, a 6-carbon, a 7-carbon, and the like, aliphatic and/or aromatic cyclic compound, including a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure, comprising a substituent R group, wherein the R group can be present or absent, and when present, one or more R groups can each be substituted on one or more available carbon atoms of the ring structure.
  • n is an integer generally having a value ranging from 0 to the number of carbon atoms on the ring available for substitution.
  • Each R group if more than one, is substituted on an available carbon of the ring structure rather than on another R group.
  • the structure above where n is 0 to 2 would comprise compound groups including, but not limited to: and the like.
  • a dashed line representing a bond in a cyclic ring structure indicates that the bond can be either present or absent in the ring. That is, a dashed line representing a bond in a cyclic ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.
  • alkyl e.g. , "alkyl,” “heteroalkyl,” “cycloalkyl, and “heterocycloalkyl”, “aryl,” “heteroaryl,” “phosphonate,” and “sulfonate” as well as their divalent derivatives
  • alkyl e.g. , "alkyl,” “heteroalkyl,” “cycloalkyl, and “heterocycloalkyl”, “aryl,” “heteroaryl,” “phosphonate,” and “sulfonate” as well as their divalent derivatives
  • R', R", R'" and R" each may independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
  • an "alkoxy" group is an alkyl attached to the remainder of the molecule through a divalent oxygen.
  • each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present.
  • R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring.
  • -NR'R is meant to include, but not be limited to, 1- pyrrolidinyl and 4-morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and - CH 2 CF 3 ) and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like).
  • haloalkyl e.g., -CF 3 and - CH 2 CF 3
  • acyl e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like.
  • Two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR') q -U-, wherein T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer of from 0 to 3.
  • two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)z-, -S(O) 2 NR'- or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') s -X'- (C"R′′′) d -, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR'-.
  • R, R', R" and R' may be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • acyl specifically includes aryl acyl groups, such as a 2-(furan-2-yl)acetyl)- and a 2-phenylacetyl group.
  • acyl groups include acetyl and benzoyl.
  • alkoxyl or “alkoxy” are used interchangeably herein and refer to a saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) group attached to the parent molecular moiety through an oxygen atom, wherein the terms “alkyl,” “alkenyl,” and “alkynyl” are as previously described and can include C 1-20 inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n -butoxyl, sec -butoxyl, tert -butoxyl, and n -pentoxyl, neopentoxyl, n -hexoxyl, and the like.
  • alkoxyalkyl refers to an alkyl-O-alkyl ether, for example, a methoxyethyl or an ethoxymethyl group.
  • Aryloxyl refers to an aryl-O- group wherein the aryl group is as previously described, including a substituted aryl.
  • aryloxyl as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxyl substituted phenyloxyl or hexyloxyl.
  • Alkyl refers to an aryl-alkyl-group wherein aryl and alkyl are as previously described, and included substituted aryl and substituted alkyl.
  • exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.
  • Alkyloxyl refers to an aralkyl-O- group wherein the aralkyl group is as previously described.
  • An exemplary aralkyloxyl group is benzyloxyl, i.e., C 6 H 5 -CH 2 -O-.
  • An aralkyloxyl group can optionally be substituted.
  • exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and tert -butyloxycarbonyl.
  • exemplary aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl.
  • An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.
  • acyloxyl refers to an acyl-O- group wherein acyl is as previously described.
  • amino refers to the -NH 2 group and also refers to a nitrogen containing group as is known in the art derived from ammonia by the replacement of one or more hydrogen radicals by organic radicals.
  • acylamino and “alkylamino” refer to specific N-substituted organic radicals with acyl and alkyl substituent groups respectively.
  • aminoalkyl refers to an amino group covalently bound to an alkylene linker. More particularly, the terms alkylamino, dialkylamino, and trialkylamino as used herein refer to one, two, or three, respectively, alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom.
  • alkylamino refers to a group having the structure -NHR' wherein R' is an alkyl group, as previously defined; whereas the term dialkylamino refers to a group having the structure -NR'R", wherein R' and R" are each independently selected from the group consisting of alkyl groups.
  • trialkylamino refers to a group having the structure -NR'R"R"', wherein R', R", and R′′′ are each independently selected from the group consisting of alkyl groups. Additionally, R', R", and/or R'" taken together may optionally be -(CH 2 ) k - where k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidino, trimethylamino, and propylamino.
  • the amino group is -NR'R", wherein R' and R" are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • alkylthioether and thioalkoxyl refer to a saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S- and alkynyl-S-) group attached to the parent molecular moiety through a sulfur atom.
  • thioalkoxyl moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
  • Acylamino refers to an acyl-NH- group wherein acyl is as previously described.
  • “Aroylamino” refers to an aroyl-NH- group wherein aroyl is as previously described.
  • Carboxyl refers to the -COOH group. Such groups also are referred to herein as a “carboxylic acid” moiety.
  • halo refers to fluoro, chloro, bromo, and iodo groups. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • hydroxyl refers to the -OH group.
  • hydroxyalkyl refers to an alkyl group substituted with an -OH group.
  • mercapto refers to the -SH group.
  • oxo as used herein means an oxygen atom that is double bonded to a carbon atom or to another element.
  • nitro refers to the -NO 2 group.
  • thio refers to a compound described previously herein wherein a carbon or oxygen atom is replaced by a sulfur atom.
  • thiohydroxyl or thiol refers to a group of the formula -SH.
  • sulfide refers to compound having a group of the formula -SR.
  • sulfone refers to compound having a sulfonyl group -S(O 2 )R.
  • sulfoxide refers to a compound having a sulfinyl group -S(O)R
  • ureido refers to a urea group of the formula -NH-CO-NH 2 .
  • Certain compounds of the present disclosure may possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as D- or L- for amino acids, and individual isomers are encompassed within the scope of the present disclosure.
  • the compounds of the present disclosure do not include those which are known in art to be too unstable to synthesize and/or isolate.
  • the present disclosure is meant to include compounds in racemic, scalemic, and optically pure forms.
  • Optically active (R)- and (S)-, or D- and L-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefenic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures with the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or I4 C-enriched carbon are within the scope of this disclosure.
  • the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • the compounds of the present disclosure may exist as salts.
  • the present disclosure includes such salts.
  • Examples of applicable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g. (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures, succinates, benzoates and salts with amino acids such as glutamic acid.
  • These salts may be prepared by methods known to those skilled in art.
  • base addition salts such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent or by ion exchange.
  • acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.
  • Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
  • the present disclosure provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure.
  • prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • the term "about,” when referring to a value can be meant to encompass variations of, in some embodiments, ⁇ 100% in some embodiments ⁇ 50%, in some embodiments ⁇ 20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1%, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.
  • Novel ⁇ -lactam antibacterials have been developed that contain a bicyclic penem core bearing substituents at C-2 and C-6. Using kinetics and x-ray structural studies, it was verified that these compounds bind to L,D-transpeptidases (enzymes involved in the biosynthesis of the peptidoglycan layer that are distinct from classical D,D-transpeptidases) of several bacterial pathogens important to human health.
  • the pathogens include Gram-positive, Gram-negative and acid-fast bacteria. Potent antimicrobial activity has been observed.
  • the presently disclosed subject matter provides synthetic small molecules whose structures are recognized by the active sites of L,D-transpeptidases, and in many instances D,D-transpeptidases as well, to compete with the normal cellular substrates involved in bacterial cell wall biosynthesis and inactivate these key cell wall cross-linking enzymes.
  • the chemical properties of the inhibitor molecules are such that they react with the catalytic amino acid residues of the transpeptidases to acylate them and, thereby, inactivate them. As a consequence of this reaction, some involving further molecular cleavages and rearrangements, all or part of the original molecule remains covalently bound to the enzyme and blocks its function and inhibit bacterial growth.
  • a sterile 96-well plate 100 ⁇ L of culture broth and a test compound are added in such a way that consecutive wells (across a row or column) contain 2 fold dilutions of the test compound.
  • 100 ⁇ L of the bacterial suspension is added to each well, the plate is incubated under appropriate conditions and growth or lack thereof is assessed at a defined time point.
  • M. tuberculosis the end point reading was taken at 2 weeks.
  • M. abscessus the end point reading was taken at 3 days, and for the rest of the pathogens the end point reading was obtained after overnight incubation according to the Clinical and Laboratory Standards Institute recommendations (Desmond, 2011).
  • the Celite filter pad contains trace amounts of methyl tert-butyl ether in addition to large quantities of residual sodium hydride. This cake will spontaneously combust and on this scale can cause a significant flame. Great care must be taken to remove as much ether as possible.
  • the organic layer was separated and washed twice with sodium bicarbonate (100 mL), dried with anhydrous sodium sulfate, filtered, diluted with heptanes (250 mL) and concentrated in vacuo. Once the majority of solvent is removed, additional heptanes (250 mL) is added and concentrated in vacuo to completion to ensure that no methyl tert-butyl ether remains.
  • the crude oil is dissolved in 400 mL isooctanes and crystallized at 4°C for 16-24 h to provide 1 as yellow needles (45.8 g, 53%).
  • the crude oil was purified by silica gel chromatography (methanol:dichloromethane, 1:40) to provide 5b as a yellow oil that became a glass under high vacuum (2.85 g, 50%).
  • 5b: TLC (methanol:dichloromethane, 1:19) 0.3.
  • the solution was diluted with water (500 ⁇ L) and dichloromethane (400 ⁇ L), washed three times with dichloromethane (5 mL) and the aqueous layer was added directly to a column of Diaion polystyrene resin (5 mL) and was eluted with water and the product-containing fractions were lyophilized to provide T400 as a white powder.
  • tuberculosis Ldt Mt1 and Ldt Mt2 enzymes were incubated with equimolar mixtures of faropenem, doripenem, biapenem and tebipenem and assessed the identities and abundance of acyl-enzyme adducts (created when the ⁇ -lactam ring reacts with the active site cysteine) using ultra performance liquid chromatography-mass spectrometry (UPLC-MS).
  • UPLC-MS ultra performance liquid chromatography-mass spectrometry
  • the faropenem adduct was again the only species detected when an equimolar mixture of oxacillin, cephalexin and faropenem was reacted with Ldt Mt2 or a penicillin binding protein DacB2 (results not shown). Additionally, while carbenicillin failed to bind to Ldt Mt2 it formed a +379 Da adduct with DacB2. These L,D-transpeptidase/ ⁇ -lactam interactions were also evaluated by isothermal titration calorimetry (ITC).
  • ITC isothermal titration calorimetry
  • Ldt Mab1 two L,D-transpeptidase orthologues in the acid-fast bacillus Mycobacterium abscessus (Ldt Mab1 , Ldt Mab2 ) and one orthologue each in the following Gram-negative ESKAPE pathogens: Klebsiella pneumoniae (Ldt Kp ), Enterobacter cloacae (Ldt Cl ), and Pseudomonas aeruginosa (Ldt Pa ) were identified and subsequently cloned (results not shown).
  • Ldt Kp Klebsiella pneumoniae
  • Ldt Cl Enterobacter cloacae
  • Ldt Pa Pseudomonas aeruginosa
  • Ldt Mt2 As an additional verification, the activity of Ldt Mt2 following incubation with penicillins (amoxicillin and ampicillin), cephalosporins (cefoxitin, cefotaxime, cephalexin, cephalothin and cefdinir), and carbapenems (doripenem and biapenem) and the penem faropenem has been assessed. While imipenem, biapenem and faropenem robustly inhibited the ability of Ldt Mt2 to hydrolyze nitrocefin, only one cephalosporin, namely cephalothin, showed comparable inhibitory activity and the remaining cephalosporins and penicillins exhibited little or no effect on the enzyme ( FIG. 1B ).
  • tuberculosis-infected BALB/c mice and these drugs were administered both alone and in combination with rifampin, a key first-line anti-TB drug.
  • Mice were infected by aerosol with M. tuberculosis H37Rv with an implantation of 3.7 log 10 colony-forming units (CFUs) in the lungs; treatment was initiated two days after infection and administered daily for three weeks.
  • CFUs colony-forming units
  • the untreated control mice developed severe disease and either died or were moribund by eighteen days post-infection.
  • the bacterial load in the lungs of mice receiving isoniazid-containing control regimens decreased significantly during the first week of treatment ( FIG. 1C ).
  • the catalytic core of Ldt Mt2 is flanked by two cavities, an inner and outer.
  • the faropenem adduct is bound in the inner cavity of the Ldt Mt2 active site; this adduct lacked the ⁇ -lactam ring, the adjoining 5-membered ring and the R1 group initially present in the drug ( FIG. 2A ).
  • UPLC-MS UPLC-MS
  • the hydroxyethyl substituent (R2) established hydrogen-bonding interactions with the side chain of Tyr318 (both direct and water mediated) and with the backbone carbonyl of Ser331.
  • the carbon adjacent to the hydroxyethyl substituent also displayed hydrophobic packing with the ⁇ -carbon of His352.
  • a 86 Da adduct covalently attached to the catalytic Cys226 (equivalent to Cys354 in Ldt Mt2 ) at a 110° angle could be modeled into the density ( FIG. 2B ).
  • the same adduct established different interactions in the active site of Ldt Mt1 .
  • His208 (equivalent to His336 of Ldt Mt2 ) did not interact with the sulfur of Cys226 but instead engaged the carbonyl C7 oxygen in the faropenem adduct via electrostatic interactions.
  • the hydroxyethyl side chain and the adjacent carbon of the adduct were stabilized by hydrophobic packing with two methylenes of the Met175 side chain and with the ⁇ -carbon of His224 (equivalent to His352 of Ldt Mt2 ).
  • the hydroxyl group of the adduct formed a hydrogen bond with the phenol side chain of Tyr190 (equivalent to Tyr318 of Ldt Mt2 ).
  • the orientation of doripenem bound to Ldt Mt2 differed from that of faropenem: the doripenem adduct of 123 Da (Table 1) bound covalently to Cys354 but extended into the outer cavity and interacted with Trp340 ( FIG. 2C ).
  • Doripenem was highly rearranged, lacking its R1 and R2 substituents and its ⁇ -lactam ring opened (C7 bound to Cys354), and could be modeled into the electron density.
  • the C2 methyl on the pyrrolidine ring and the adjacent carbon in that ring of the adduct demonstrated van der Waals interactions with Trp340.
  • the side chain of Tyr318 and the backbone amide nitrogen of Cys354 formed hydrogen bonds with the carbonyl C7 oxygen.
  • the amino N4 of the pyrrolidine ring formed a hydrogen bond with the side-chain of His352.
  • Stable adducts could be detected for biapenem with wild-type Ldt Mt2 , but no adducts could be detected for any of the mutant proteins, indicating that all four amino acids were involved in binding biapenem.
  • Faropenem and tebipenem failed to produce adducts with mutants H336N, H336A, C354S or C354A but did produce stable adducts with the Y318F, Y318A, and H352A (H352N with faropenem only).
  • the R1 chain was replaced with various groups identified by naive Bayesian machine-learning models as the most frequent sulfur substituents in M. tuberculosis growth inhibitors (Ekins, et al., 2013), and initially focused on the 2-substituted analogs of existing carbapenems with an emphasis on R1 substituent to disrupt critical residues in the catalytic site of L,D-transpeptidases. Synthesis of the final carbapenems followed a two-stage process (not shown) where the enol phosphate and thiol (or immediate precursor) were reacted to afford the desired thioether. The 4-nitrobenzyl ester protecting group was then cleaved to yield the desired carbapenem.
  • tuberculosis namely T205, T206, T208 (all MICs 1-2 ⁇ g/mL) and T210 (MIC 0.25-0.5 ⁇ g/mL)
  • T208 and T210 were reacted with Ldt Mt2 and quantified the adducts at 1 and 24 hrs.
  • Ldt Mt2 in complex with evolved carbapenems The evolved carbapenems also provided new insights to improve the ability to maximize the antimicrobial, and specifically the anti-TB activity, of this class of drugs.
  • the crystal structures of Ldt Mt2 in complex with T206, T208, T210 and T224 were therefore solved ( FIG. 4 ).
  • T206 binds in three different orientations in the active site of the enzyme, via the outer cavity (conformation A1) or via the inner cavity (conformation A2 and B), from two different crystal structure forms, Ldt Mt2 -T206-A and Ldt Mt2 -T206-B.
  • the electron density map of T206 in conformation A1 in chain A shows this carbapenem interacting with the outer cavity and covalently attached to the catalytic Cys354 ( FIG 4A ).
  • the electron density of carbapenem T206 is contiguous to the S ⁇ atom of Cys354, but it is missing for much of the R1 group beyond the thioether sulfur.
  • the hydroxyl of the R2 group hydrogen bonds with the side chain of Tyr318 and displayed both a direct and a water-mediated hydrogen bond with the backbone carbonyl of Gly332.
  • the carboxyl group at C3 of the pyrrolidine ring forms a hydrogen bond with the side chain of Trp340 and with the backbone amide of His352.
  • Trp340 also has hydrophobic interactions with the alkyl tail of the R1 group of T206.
  • T206 In conformation A2, chain B of Ldt Mt2 -T206-A, T206 is bound in the inner cavity resembling the meropenem-bound structure (PDB ID 3VYP) (Li, et al., 2013), but the R2 group tail makes additional extensive electrostatic and hydrophobic interactions with Ala288, Tyr292, Leu385 and Pro386 ( FIG 4B ).
  • the C3 carboxyl group accepts a hydrogen bond from Tyr318, and Met303 has a hydrophobic interaction with the terminal carbon of the C6 hydroxyethyl side chain.
  • the pyrrolidine ring and its carboxylate substituent have a conformation similar to the corresponding substructure of meropenem in chain A (PDB ID: 4GSU) (Kim, et al., 2013) and in conformation A of chain A (PDB ID: 3VYP) (Li, et al., 2013), but this ring was rotated with respect to the orientation observed in the other chains of 4GSU and 3VYP.
  • T206 is fully ordered in conformation B, with its R1 group tail stabilized by hydrophobic interactions with residue Thr285 and by a network of water-mediated hydrogen bonds between the carboxylate of T206 and the side-chain Ser331, the backbone amide nitrogen of Ala288, and the backbone carbonyl oxygen of Pro286.
  • T208, T210 and T224 forms the same quaternary interactions with the outer cavity of Ldt Mt2 , and their C3 carboxyl accepts hydrogen bonds from Trp340 and Asn356 side chains thereby mimicking those found in T206 conformation A1.
  • C3 carboxyl accepts hydrogen bonds from Trp340 and Asn356 side chains thereby mimicking those found in T206 conformation A1.
  • electron densities for the methyl group of the pyrrolidine ring at C1 position and the R1 group tail beyond the thioether sulfur are missing.
  • ⁇ -lactams D,D-transpeptidases.
  • resistance to ⁇ -lactams has traditionally been attributed to ⁇ -lactamases, most of which have evolved as soluble ⁇ -lactam hydrolases from their membrane-bound D,D-transpeptidase ancestors (Meroueh, et al., 2003).
  • L,D-transpeptidases are biochemically and structurally distinct from D,D-transpeptidases and use cysteine to catalyze the formation of non-classical 3 ⁇ 3 linkages in the peptidoglycan and thereby provide an alternative mechanism by which bacteria can survive in the presence of traditional D,D-transpeptidase-targeting ⁇ -lactams (Mainardi, et al., 2005). Therefore, molecules that can also target the L,D-transpeptidases have significant potential as agents with bactericidal activity against organisms that utilize both classical and non-classical transpeptidases when causing human disease.
  • penem and carbapenem ⁇ -lactam antibacterials have potent anti-TB activity using a preclinical mouse model of TB treatment.
  • the bioavailability of many carbapenems is sub-optimal due to metabolism by dehydropepetidase-1 (DHP-1) in the renal proximal tubules (Hikida, et al., 1992).
  • DHP-1 dehydropepetidase-1
  • Faropenem and early carbapenems meropenem and imipenem exhibit limited activity in mice infected with M. tuberculosis (Dhar, et al., 2015; Chambers, et al., 2005; Veziris, et al., 2011; England, et al., 2012).
  • NCT02349841 demonstrated a promising early bactericidal activity of meropenem in TB patients (Diacon, et al., 2016).
  • biapenem is more potent against M . tuberculosis (Kaushik, et al., 2015) and is resistant to inactivation by DHP-1 (Hikida, et al., 1992).
  • DHP-1 Hybrida, et al., 1992
  • the anti-tubercular activity seen in the mouse model in this work suggests that new and evolved (carba)penems have promise in treatment of TB.
  • an in-depth biochemical and structural analyses of (carba)penem interactions with M In pursuit of developing new carbapenems, an in-depth biochemical and structural analyses of (carba)penem interactions with M.
  • tuberculosis L,D-transpeptidases was conducted allowing for the development of evolved carbapenems with improved anti-TB activity.
  • reaction of the carbapenem doripenem at the Ldt M2 catalytic center takes a different course, but not one driven by the formation of a stable (aromatic) pyrrole ring of unchanged oxidation state as expected. Instead, formation of the net two-electron reduced pyrrolinium adduct hydrogen-bonded to the nearby His352 was observed. Specifically, attack of the active site cysteine on the carbapenem carbonyl is proposed to form an imine/iminium species, which may decarboxylate to a stabilized ylid, analogous to the active form of the cofactor thiamin.
  • the resulting pyrrolinium may be captured by the adjacent thioether and the resulting bridged sulfonium species, either by attack of a nucleophile or by reversible release of the enamine and scavenge of the sulfonium ion, achieves both the required two-electron reduction and preservation of the C1 and C5 stereocenters evident in the crystal structure. Subsequent to these events, or earlier, precedented retro-aldol reaction can ensue to expel the hydroxyethyl side chain as acetaldehyde (Hugonnet, et al., 2009; Drawz, et al., 2010).
  • Cordillot M. et al. In vitro cross-linking of peptidoglycan by Mycobacterium tuberculosis L,D-transpeptidases and inactivation of these enzymes by carbapenems. Antimicrobial agents and chemotherapy, doi:10.1128/AAC.01663-13 (2013 ).
  • the Mycobacterium tuberculosis protein LdtMt2 is a nonclassical transpeptidase required for virulence and resistance to amoxicillin. Nature medicine 2010; 16:466-9 .

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Claims (8)

  1. Un composé de formule (Ic) :
    Figure imgb0033
     où :
    P est -N(R6)- ; et
    R6 est
    Figure imgb0034
    - - - représente une liaison simple ou double ;
    et des stéréoisomères et sels pharmaceutiquement acceptables de celui-ci.
  2. Le composé de la revendication 1, où le composé de formule (Ic) est :
    Figure imgb0035
  3. Un composé de l'une quelconque des revendications 1 ou 2, ou un stéréoisomère ou sel pharmaceutiquement acceptable de celui-ci, pour son utilisation dans le traitement ou la prévention d'une infection bactérienne chez un sujet.
  4. Le composé, ou le stéréoisomère ou sel pharmaceutiquement acceptable de celui-ci, pour l'utilisation de la revendication 3, où l'infection bactérienne est sélectionnée dans le groupe constitué d'infections à M. tuberculosis, M. abscessus, A. baumannii,
    S. aureus, K. pneumoniae, E. cloacae, P. aeruginosa et E. faecalis, et de combinaisons de celles-ci.
  5. Le composé, ou le stéréoisomère ou sel pharmaceutiquement acceptable de celui-ci, pour l'utilisation de la revendication 3, où l'infection bactérienne est une ou plusieurs souches de bactéries qui sont résistantes à des agents antimicrobiens dirigés vers la D,D-transpeptidase inactive.
  6. Un procédé d'inhibition de la croissance d'une bactérie in vitro comprenant la mise en contact de la bactérie avec une quantité efficace d'un composé de l'une quelconque des revendications 1 ou 2, ou d'un stéréoisomère ou sel pharmaceutiquement acceptable de celui-ci.
  7. Une composition pharmaceutique comprenant un composé de formule (Ic) de l'une quelconque des revendications 1 ou 2 et un véhicule pharmaceutiquement acceptable.
  8. La composition pharmaceutique de la revendication 7, la composition pharmaceutique comprenant un ou plusieurs autres composés antimicrobiens.
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